Distinct molecular features and potential therapeutic strategies for spinal cord gliomas.
Authors: Frances Elaine Chow, Joanne Xiu, Patricia Pittman, Edith Yuan, Tania Vartanians, Phillip Walker, Theodore Nicolaides, Michael J. Glantz, Ashley Love Sumrall, Sonikpreet Aulakh, David M. Ashley, David Spetzler, Lindsay Hwang, Jason Chao Ye, Eric L. Chang, James S Hu, Frank J. Attenello, Josh Neman, David D. Tran, Gabriel Zada
Journal: Journal of Clinical Oncology (2023)

2056 Background: Spinal cord gliomas (SCG) are rare primary CNS tumors with varied prognosis. Standard treatment remains poorly defined, as no clear survival advantage exists with extensive resection, radiation, or chemotherapy. Mounting evidence suggests that tumors from different regions of the CNS harbor unique molecular signatures. In a retrospective study, we comprehensively characterized molecular alterations to identify potential therapeutic strategies in the largest cohort of SCG reported to date. Methods: We performed centralized pathology review and analyzed SCG with next-generation sequencing of DNA (592 gene NextSeq or WES, Novaseq), RNA (WTS, NovaSeq) and pyrosequencing (MGMT promoter methylation, MGMTme). We estimated tumor microenvironment cell infiltration by quanTIseq &amp; Epithelial-Mesenchymal Transition (EMT) by RNAseq. We used X2/Fisher’s-exact/Mann-Whitney U tests for comparison &amp; determined significance (p &lt; 0.05), adjusting for multiple comparison by the Benjamini-Hochberg method (q &lt; 0.05). Results: We analyzed 39 surgically accessible SCG (19 high grade, 17 low grade, 3 NOS); ependymomas were excluded. The most common alterations were mutations in H3F3A (31%), TP53 (25%), ATRX (21%), NF1 (18%) &amp; BRAF fusion (19%). H3F3A mutations occurred exclusively in high grade SCG (63%, q &lt; 0.05) while BRAF fusions occurred exclusively in low grade SCG (60%, p &lt; 0.05). TP53 mutations were more prevalent in high grade SCG (50% vs. 8%, p &lt; 0.05). Compared to intracranial gliomas (n = 6732), SCG harbor significantly more frequent H3F3A (31% vs. 1.6%), KRAS mutations (10% vs. 0.7%) &amp; BRAF fusions (19% vs. 0.7%) but less frequent TERT (4.3% vs. 66%) &amp; PTEN (0 vs. 27%) mutations or EGFR amplification (0 vs. 28%) (all q &lt; 0.05). SCG rarely harbor the canonical intracranial alterations IDH1 (2.6% vs. 17%), EGFRvIII (0 vs. 17%) or MGMTme (19% vs. 47%) (p &lt; 0.05). SCG have greater penetration of immune infiltrates of DCs (median cell fraction/MCF: 13% vs. 9%), T regs (positive percent: 47% vs. 26%) &amp; B cells (MCF: 9% vs. 7%), with less penetration of monocytes (MCF: 0 vs. 2%) (q &lt; 0.05). EMT score associates with high grade glioma in intracranial disease (q &lt; 0.05) but does not recapitulate in SCG (p &gt; 0.05). Conclusions: Clinical management of SCG is currently drawn from experience with intracranial gliomas. Our results identify unique molecular features of SCG suggesting an underlying biology distinct from intracranial gliomas. In SCG, H3F3A mutations are exclusive to high grade while BRAF fusions are exclusive to low grade; SCG rarely harbor canonical intracranial alterations such as IDH1, EGFR or MGMTme; and SCG have greater penetration of DCs with less penetration of monocytes. We provide a biological explanation for limited effectiveness of current therapies in SCG with potential implications for chemotherapy, targeted and immunotherapy. Our work underscores the need for investigations dedicated uniquely to SCG.